A subset of prostate basal cells lacks the expression of corresponding phenotypic markers.
ABSTRACT Immunohistochemical staining for cytokeratin (CK) 34ssE12 has been routinely used to elucidate prostate basal cells for differentiation between non-invasive and invasive lesions. Our previous studies, however, revealed that some morphologically distinct basal cells observed on H&E-stained sections completely lacked CK34ssE12 expression. Our current study attempted to assess whether these basal cells would also lack the expression of other phenotypic markers, and whether basal cell alterations would affect the proliferation status of the associated tumor cells. Consecutive sections from prostate tumors with large basal cell clusters that were morphologically distinct in H&E sections but were completely negative for CK 34ssE12 were morphologically and immunohistochemically assessed with a panel of basal cell phenotypic and other markers. In addition to CK 34ssE12, these basal cells also completely lacked the expression of other phenotypic markers, including CK5, CK14, p63, and maspin, in contrast to adjacent basal cells, which were strongly positive for these markers. Tumors surrounded by basal cell layers that lack the expression of basal cell phenotypic markers showed a significantly higher rate of cell proliferation and mast cell infiltration than their counterparts. These findings suggest that basal cells might be targets of a variety of pathological alterations, which could significantly impact biological presentations of associated tumor cells.
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ABSTRACT: The development of breast cancer is believed to be a multi-step process, sequentially progressing from normal to hyperplastic, to in situ, and to invasive stages. The progression from the in situ to invasive stage is believed to be triggered primarily, if not solely, by the overproduction of proteolytic enzymes by cancer cells, which cause degradation of the basement membrane. This theory is consistent with data derived from studies with cell cultures or animal models, while results from recent worldwide clinical trials with a variety of proteolytic enzyme inhibitors have been very disappointing, casting doubt on the validity of the enzyme theory. Based on our recent studies, we propose that breast tumor invasion is triggered by the following mechanisms and events: (1) the predisposition of genetic abnormalities in ME cell replenishment-related genes or other insults results in elevated focal degeneration of ME cells in some individuals; (2) the degradation products of ME cells or diffusible molecules of epithelial cells attract infiltration of immunoreactive cells (IRC) into the affected sites; (3) the direct physical contact between IRC and degenerated ME cells results in the discharge of digestive enzymes from IRC, causing focal disruptions in the ME cell layer; (4) focal disruptions in a given ME cell layer result in a localized loss of tumor suppressors and paracrine inhibitory function, a focal increase of permeability for oxygen, nutrients, and growth factors, and a localized increase of leukocyte infiltration, which facilitate the monoclonal proliferation of tumor progenitors, forming a biologically more aggressive cell cluster overlying the disrupted ME cell layer; (5) the direct physical contact between the newly formed cell cluster and stromal cells stimulates the production of tenascin and other invasion-associated molecules that facilitate tissue remodeling, angiogenesis, and epithelial-mesenchymal transition, providing a favorable micro-environment for proliferation and invasion. Our hypothesis differs from the enzyme theory in the stage of tumor invasion, the cellular origin of invasive lesions, the significance of IRC and stromal cells, and the potential approaches for treatment and prevention. If confirmed, our hypothesis could facilitate the early detection of specific individuals at increased risk to develop invasive breast cancer. More importantly, our hypothesis may facilitate development of novel approaches, including stimulating ME cell growth, neutralizing ME cell degradation products, manipulating the types and extent of IRC infiltration, and controlling the extent of stromal reactions, to combat tumor invasion.Medical Hypotheses 02/2007; 69(6):1340-57. DOI:10.1016/j.mehy.2007.02.031 · 1.15 Impact Factor
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ABSTRACT: Benign prostatic hyperplasia and prostatic adenocarcinoma exhibit prominent zonal predilections. Basal cells from the transitional zone and from the peripheral zone are postulated to have different underlying biological properties. We studied basal cells in both prostatic zones. Tissue microarrays (TMA) were prepared from 65 whole-mounted prostatectomy specimens with prostatic adenocarcinoma. The transitional zone and peripheral zone were sampled from each prostate. TMA sections were stained with a basal cell cocktail (CK 34betaE12 + p63). The immunostaining pattern and the morphology of basal cells were recorded. Triangular-shaped basal cells were highlighted by CK 34betaE12 cytoplasmic and p63 nuclear staining. These basal cells had their long axis oriented perpendicular to the basement membrane and their apex toward the lumen interdigited between secretory luminal cells. This morphology was seen in the majority of peripheral zone benign prostatic glands (92.0%) but only a minority of transitional zone benign prostatic glands (18.0%). Basal cells of the transitional zone showed weak or absent CK 34betaE12 staining in 65.9% of glands while maintaining p63. All glands with high-grade prostatic intraepithelial neoplasia (HGPIN) contained the triangular basal cells. In addition, basal cell clusters were identified in 8.7% of peripheral zone glands and 5.2% of HGPIN glands. Our results indicate that the basal cell morphology and the basal cell immunophenotype have a zonal variation. The finding of a unique morphology of basal cells and the presence of basal cell clusters in the peripheral zone suggests that the peripheral zone might be the stem/progenitor cell-rich area in the human prostates.The Prostate 11/2007; 67(15):1686-92. DOI:10.1002/pros.20658 · 3.57 Impact Factor
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ABSTRACT: Predicting tumor behavior in meningiomas based on morphologic features alone remains difficult. The present study was undertaken to assess the correlation between p63 expression and histological grade of meningiomas. A total of 37 archival intracranial meningiomas were classified into 20 grade I, 13 grade II, and 4 grade III meningiomas. Using immunohistochemical methods, staining was scored based on nuclear and/or cytoplasmic distribution as follows: 0, no staining; 1, 50% or less of the cells; 2, more than 50% of the cells. Of grade I meningiomas, 95% (19/20) lacked nuclear p63 expression and none exhibited cytoplasmic staining. Overall, 92% of grade II tumors showed nuclear expression and 31% (4/13) showed cytoplasmic expression. Grade III tumors showed an overall nuclear expression of 75% (3/4) with all exhibiting cytoplasmic staining. Our results indicate a good correlation exists between histological grade and p63 protein expression, suggesting that p63 expression might be correlated with the clinical outcome.International Journal of Surgical Pathology 02/2008; 16(1):38-42. DOI:10.1177/1066896907306772 · 0.96 Impact Factor